In patients with follicular lymphoma who received at least one prior line of therapy, the combination of the bispecific antibody epcoritamab-bysp and rituximab–lenalidomide (R2) reduced the risk of disease progression or death by almost 80% over R2 alone, based on the primary analysis of the phase III EPCORE FL-1 trial.1 The findings from this first randomized trial to test a bispecific antibody combination in follicular lymphoma, suggest the novel chemotherapy-free combination could offer an effective alternative to chemotherapy that can be safely administered on an outpatient basis.
The results, which were concurrently published in The Lancet,2 led to the November 2025 regulatory approval of epcoritamab plus R2 for relapsed or refractory follicular lymphoma. Epcoritamab, a CD3 x CD20 bispecific antibody, was previously approved as monotherapy after two or more prior lines of treatment. R2 is a standard second-line treatment for follicular lymphoma, and unique among CD3 x CD20 T-cell engagers, epcoritamab has minimal interference with rituximab’s antitumor activity when combined with it in preclinical studies.
Lorenzo Falchi, MD, Assistant Attending Physician, Memorial Sloan Kettering Cancer Center, New York, described the substantial increase in progression-free survival and response rate with the regimen—meeting the study’s coprimary endpoints—along with improvements in depth of response and duration of disease control over R2 alone at the 2025 American Society of Hematology (ASH) Annual Meeting & Exposition.
“There are multiple components to deciding when to treat and what to treat with, depending on the patient in front of you, your familiarity with particular treatments, and obviously the data, but I think the data are compelling enough to make epcoritamab–R2 a benchmark for a standard of care,” said Dr. Falchi.
EPCORE FL-1 Details
The study randomly assigned 488 patients with relapsed or refractory follicular lymphoma after one or more prior lines of therapy to receive fixed-duration epcoritamab 48 mg plus R2 or R2 alone for up to 12 cycles. Approximately 60% of patients had received one line and approximately 20% had prior bendamustine.
At a median follow-up of 14.8 months, progression-free survival more than doubled with epcoritamab plus R2. At 16 months, 85.5% of that arm remained progression-free as compared with 40.2% of the control arm (hazard ratio [HR] = 0.21; P < .0001). (Note: The hazard ratio applies to the whole curve, and not just the 16-month mark.) Median progression-free survival was not reached with epcoritamab–R2 and was 11.7 months with R2 alone.
“We also observed a positive trend for overall survival favoring epcoritamab–R2 at this early time point, with 10 events recorded in the epcoritamab–R2 arm and 25 in the R2 arm,” he said.
Median overall survival was not reached in either arm (HR = 0.38, 95% confidence interval [CI] = 0.18–0.80; P = .0039, at a one-sided significance level of 0.000005).
Meeting the second primary endpoint, the group treated with epcoritamab–R2 showed a significantly higher overall response rate, 95% vs 79%, with higher overall complete response rates as well, 83% vs 50% (P < .001). Responses were reported to be durable, with median duration of response not reached with epcoritamab–R2 vs 11.5 months with R2 alone (HR = 0.19; P < .0001). Epcoritamab–R2 also extended the time to the next antilymphoma treatment; the median was not reached with epcoritamab–R2 and was 24.3 months with R2 alone (HR = 0.15; P < .0001). At 16 months, 93% vs 65% of patients were free from subsequent therapy, Dr. Falchi reported.
The results appeared to be consistent across all subgroups analyzed. “We demonstrated that both in the low- and higher-risk patients, the magnitude of benefit with epcoritamab–R2 compared with R2 is preserved,” he said.
Safety Profile
“Neutropenia and infections were manageable, and few patients discontinued any drug because of these [events]. Fatal events were rare. And despite higher rates of adverse events in the epcoritamab–R2 arm, most patients completed the prescribed regimen, at a median relative dose intensity of at least 90% for epcoritamab–R2,” he said.
Notable adverse events with epcoritamab–R2 and R2 alone, respectively, included:
- Serious adverse events: 56% vs 29%;
- Adverse events leading to treatment discontinuation: 19% vs 12%;
- Neutropenia: 74% (grade ≥ 3: 69%) vs 52% (42%)
- Infections: 77% (33%) vs 53% (16%);
- Cytokine release syndrome: 35% vs < 1%;
- Anemia: 28% (8%) vs 17% (5%);
- Thrombocytopenia: 28% (9%) vs 18% (6%);
The study also tested two different step-up dosing regimens for the epcoritamab–R2 combination, showing that three initial smaller doses (three-step) resulted in a reduced rate of low-grade cytokine release syndrome compared with two initial smaller doses (two-step). With two-step-up dosing, grade 1 cytokine release syndrome events occurred in 36% and grade 2 in 9%; with three-step dosing, these rates dropped to 21% and 5%, respectively. All events resolved.
One of the favorable aspects of this regimen is that it can be administered outside of the hospital setting, Dr. Falchi emphasized, noting that of the 6,000 U.S. hospitals, 5,100 are community-based. Treatment access at these locations is important to patients, he said.
“The prospect of a subcutaneous, completely outpatient treatment that does not result in a significant [cytokine release syndrome] rate is good news, in that it gives patients the best opportunity for a response,” he commented in the post-presentation discussion period.
He said the low rate of cytokine release syndrome with epcoritamab–R2 is reassurance that such community-based treatment will be safe, acknowledging “some hesitancy to use bispecific antibodies in a community setting because of cytokine release syndrome.” The study “provides reassurance to our colleagues that may not have immediate access to an affiliated large hospital, or to patients who would have to travel long distances to be admitted or be seen in an urgent care setting,” he said.
A study is underway to test epcoritamab–R2 in a front-line setting. There is a question of whether lenalidomide may be eliminated in this regimen, and to address this, epcoritamab is also being investigated with rituximab only.
DISCLOSURE: Dr. Falchi has received research funding from Roche, Genentech, Genmab, AbbVie, Innate Pharma, BeiOne Medicines, and AstraZeneca; has served as a consult or advisor for Roche, Genentech, Genmab, AbbVie, Sanofi, AstraZeneca, Merck, NOBO Medicine, ADC Therapeutics (Seagen), Ipsen, Johnson & Johnson, Regeneron, Chugai, and Bristol Myers Squibb; has received honoraria from Roche, Genmab, AbbVie, Kite, and Chugai; and has received travel expenses from Genmab, AbbVie, Roche, Kite, and Chugai.
REFERENCES
1. Falchi L, et al: Primary phase 3 results from the epcore FL-1 trial. 2025 ASH Annual Meeting& Exposition. Abstract 466. Presented December 6, 2025.
2. Falchi L, et al: A global, open-label, randomsed phase 3 trial. Lancet (early release online, Dec.9, 2025).
EXPERT POINT OF VIEW
Elizabeth Budde, MD, PhD, Associate Professor in the Department of Hematology and Hematopoietic Cell Transplantation and Executive Medical Director, Enterprise Immune Effector Cell Program at City of Hope in Duarte, California, offered her thoughts on EPCORE FL-1 in an interview with The ASCO Post.
“I think the takeaway is that with EPCORE FL-11 we have a phase III, very high-quality study that is positive, against the commonly used R2 regimen. What I’m really excited about is that epcoritamab[-bysp] is the first bispecific CD3 x CD20 T-cell engager to officially become available in the second-line setting. I think the study will change the landscape for how we manage patients with follicular lymphoma in the second line,” she said.
Dr. Budde acknowledged that as a bispecific antibody there will be a learning curve associated with using epcoritamab. One concern has been the risk for cytokine release syndrome (CRS); in the study, grade 2 events occurred in 5% of patients undergoing three-step dosing. At least in the near future, she said, for most patients the first cycle will likely be administered in a treatment center familiar with using bispecifics and managing CRS, with the remaining treatment courses safely completed in the community.
The other second-line option is the anti-CD19 antibody tafasitamab-cxix plus R2, approved in 2025 based on the results of the inMIND trial in which tafasitamab plus R2 produced a 57% reduction in the risk of progression or death vs R2.2 Dr. Budde suggested that for physicians or centers not yet experienced in managing CRS, this regimen is a good option. “Tafasitamab did not add much toxicity to R2 alone in the study,” she noted.
“I think that if you want to give R2, you should think about adding tafasitamab, or if you’re familiar with managing CRS, give the bispecific,” she said, predicting greater uptake of tafasitamab in areas where patients lack access to inpatient care.
While the study investigators suggested that epcoritamab/R2 might be a “new benchmark,” Dr. Budde maintained that label is premature, largely because there remain obstacles to its widespread adoption. “Not every patient will have access to it. But this is another regimen to add, and to get comfortable with, and to continue to watch,” she said.
She indicated that several bispecific T-cell engagers are being evaluated for use early in the disease course, and that along with CAR-T cell therapy, they seem to be producing long, durable remissions that could be heralding a potential cure.“I’m super excited to see all these new therapies moving forward.”
DISCLOSURE: Dr. Budde is an advisory board member for AstraZeneca, BMS, Kite Pharma, Genetech/Roche, ADC Therapeutics, and Crispr Therapeutics; and has received research support from Merck, AstraZeneca, and Pepromene Bio.
REFERENCES
1. Falchi L, Nijland M, Huang H, et al. Primary phase 3 results from the EPCORE FL-1 trial. 2025 ASH Annual Meeting & Exposition. Abstract 466. Presented December 6, 2025.
2. Sehn LH, Hübel K, Luminari S, et al. Tafasitamab, lenalidomide, and rituximab in relapsed or refractory follicular lymphoma (inMIND): A global, phase 3, randomised controlled trial. Lancet (early release online February 10, 2026).
